Tobramycin is a very hygroscopic aminoglycoside antibiotic that is extracted from the fermentation of Streptomyces tenebrarius. Two major impurities and a degradation product specified in European Pharmacopeia (EP) are kanamycin B, neamine (impurities), and nebramine (degradation product), respectively. It shows an antibacterial effect on the gram-negative bacteria when formulated as ophthalmic, inhalant, and injectable dosage forms. Generally, the injectable dosage forms of tobramycin include Tobramycin Injection and Tobramycin for Injection. The former one is a tobramycin sulfate solution with the addition of preservatives and anti-oxidants, and the latter one is tobramycin sulfate powder without any other excipients. As the Tobramycin for Injection is concerned, it is generally prepared by lyophilizing (freeze-drying) a sterile tobramycin sulfate solution. Although the lyophilization process for powder for injection is well-developed in pharmaceutical industry, it is still inefficient on drying and requires high energy consumption. Moreover, low throughput is another demerit due to the long cycle time, i.e., about 24 to 48 h. Thus, the lyophilization process is essentially time-consuming and expensive.
Spray drying is one of the conventional techniques in chemical industry since 1920s and has several advantages, compared to the lyophilization process. For example, the spray drying process can save more than 50% energy cost in comparison to the lyophilization process. Generally, the spray drying process mainly includes three stages. The first one is the atomization of the concentrated solution into numerous liquid droplets. Second, the liquid droplets contact with the heated gas, e.g., air or N2, and then the liquid droplets evaporate to accompany with the nucleation of particles in a short period about a few seconds. Finally, the dried particles are collected by a cyclone system incorporated with a bag filter or wet scrubber. In view of industrial processes, the advantages of spray drying include the continuous mass production, automated controlling, higher energy efficiency, and feasible applications for both heat-resistant and heat-sensitive materials. Therefore, the application of spray dryers is widely adopted in industry. However, it is rarely in the aspect of manufacturing active pharmaceutical ingredients (APIs) so far.
In 2008, Pilcer had reported that tobramycin suspension can be spray dried to prepare tobramycin powder for inhalation in his dissertation. In the study, tobramycin suspensions were firstly prepared by using a homogenizer to disperse tobramycin powder into isopropanol solutions containing 0 to 20% (v/v) water. After the tobramycin suspension was spray dried, the prepared powders were filled with capsules as the tobramycin powder for inhalation. The same results were also disclosed in other publications.
The above prior art described the preparation of tobramycin powder for inhalation by spray drying a tobramycin suspension, in which isopropanol is used as continuous phase. However, the prepared tobramycin powder is different from tobramycin sulfate and not suitable for intravenous use in consideration of the residual isopropanol, which is toxic to health. Also the chosen isopropanol is a flammable solvent which increases the possibility of explosion during spray drying. In addition, isopropanol is not environmentally friendly. On the other hand, the solid content of prepared tobramycin suspension is merely 5% (w/v) which is much lower than the saturated solubility of tobramycin in water. Thus the production rate of spray drying tobramycin is quite low and impractical. Moreover, the injectable dosage form, i.e., powder for injection, is used more widely in comparison to the dry powder inhalation (DPI) due to its effectiveness and ready-to-use.
Accordingly, the present invention provides a method of spray drying for preparing tobramycin sulfate powder that can be formulated as Tobramycin for Injection and reconstituted for intravenous administration.